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EP2585470A2 - Nouveaux dérivés fusionnés de pyrimidine pour l'inhibition de l'activité tyrosine kinase - Google Patents

Nouveaux dérivés fusionnés de pyrimidine pour l'inhibition de l'activité tyrosine kinase

Info

Publication number
EP2585470A2
EP2585470A2 EP11798350.2A EP11798350A EP2585470A2 EP 2585470 A2 EP2585470 A2 EP 2585470A2 EP 11798350 A EP11798350 A EP 11798350A EP 2585470 A2 EP2585470 A2 EP 2585470A2
Authority
EP
European Patent Office
Prior art keywords
phenyl
thieno
acrylamide
pyrimidin
yloxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP11798350.2A
Other languages
German (de)
English (en)
Other versions
EP2585470B1 (fr
EP2585470A4 (fr
Inventor
Mi Young Cha
Seok Jong Kang
Mi Ra Kim
Ju Yeon Lee
Ji Young Jeon
Myoung Gi Jo
Eun Joo Kwak
Kwang Ok Lee
Tae Hee Ha
Kwee Hyun Suh
Maeng Sup Kim
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hanmi Science Co Ltd
Original Assignee
Hanmi Science Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=45371929&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=EP2585470(A2) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to PL11798350T priority Critical patent/PL2585470T3/pl
Priority to SI201131094A priority patent/SI2585470T1/sl
Priority to RS20170267A priority patent/RS55783B1/sr
Priority to PL15181011T priority patent/PL2975042T3/pl
Application filed by Hanmi Science Co Ltd filed Critical Hanmi Science Co Ltd
Priority to EP15181011.6A priority patent/EP2975042B1/fr
Priority to DK15181011.6T priority patent/DK2975042T3/en
Publication of EP2585470A2 publication Critical patent/EP2585470A2/fr
Publication of EP2585470A4 publication Critical patent/EP2585470A4/fr
Publication of EP2585470B1 publication Critical patent/EP2585470B1/fr
Application granted granted Critical
Priority to HRP20170456TT priority patent/HRP20170456T1/hr
Active legal-status Critical Current
Anticipated expiration legal-status Critical

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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Definitions

  • EGFR epidermal growth factors
  • EGFR EGF receptor
  • the compounds have been known to form a covalent bond with Cystein773 (Cys773) positioned at an ATP domain of EGFR, thereby irreversibly blocking the autophosphorylation of EGFR and thus efficiently inhibiting the signal transduction of cancer cells (David W. Fry et al., Proc. Natl. Acad. Sci. U.S.A. 95, 12022, 1998), and exhibit higher inhibitory activities compared to the reversible inhibitors commercially available as dual inhibitors of EGFR/HER-2, or pan-HER inhibitors in in vitro activities and in various in vivo models of carcinomas (Jeff B. Smaill et al., J. Med. Chem. 42, 1803, 1999).
  • monocytes in which BTK activity is absent, showed decreased TNF-a production following stimulation (Horwood et al. J Exp Med. 197, 1603, 2003). Therefore, TNF-a mediated inflammation could be modulated by BTK inhibitors.
  • BTK has been reported to play a role in apoptosis as some of regulators (Islam and Smith, Immunol. Rev. 178, 49, 2000).
  • BTK inhibitors would be useful for the treatment of certain B-cell lymphomas and leukemias (Feldhahn et al., J. Exp. Med. 201, 1837, 2005).
  • JAK3 Janus kinases involving JAK3 have been widely investigated as a target for autoimmune and/or inflammatory diseases.
  • JAK3 unlike JAK2 involved in hematosis and erythrocyte homeostasis or JAKl expressed in various tissues, JAK3 is expressed in lymphocytes and plays a very important role in signal transduction via various cytokines, i.e., IL-2, IL-4, IL-7, IL-9 and IL-15, which is more attractive (Flanagan et al, Journal of medicinal Chemistry, 53, 8468, 2010).
  • JAK3 plays a role in the maturation of B-cells and T-cells as well as in maintaining T-cell functions.
  • ITK-deficient mice immune symptoms of allergic asthma were attenuated and lung inflammation, eosinophil infiltration, and mucous production in response to challenge with the allergen ovalbumin were drastically reduced (Muller et al., Journal of Immunology 170, 5056, 2003). This shows that ITK inhibitors would be useful in the treatment of asthma.
  • ITK has also been implicated in atopic dermatitis. This gene has been reported to be more highly expressed in peripheral blood T-cells from patients with severe atopic dermatitis, compared with controls or patients with mild atopic dermatitis (Matsumoto et al., International archives of Allergy and Immunology 129, 327, 2002).
  • BMX bone marrow tyrosine kinase
  • a compound for effectively inhibiting the kinases may be useful as a therapeutic agent for various inflammatory diseases, autoimmune diseases, and immunity mediated diseases.
  • W is O or S
  • X is O, NH, S, SO or SO 2 ;
  • Y is hydrogen atom, halogen atom, C ⁇ alkyl or C ⁇ alkoxy
  • a and B are each independently hydrogen atom, halogen atom, or di(Ci_ 6 alkyl)aminomethyl;
  • Z is aryl or heteroaryl having one or more substituents selected from the group consisting of: hydrogen atom, halogen atom, hydroxy, nitro, cyano, Q. 6 alkyl, C ⁇ alkoxy, C ⁇ alkylcarbonyl, C 1-6 alkoxycarbonyl, di(C 1-6 alkyl)aminoC 2- 6 alkoxycarbonyl, amino, Q . 6 alkylam.no, di(C 1 . 6 alkyl)amino, carbamoyl, C . 6 alkylcarbamoyl, di(Ci. 6 alkyl)carbamoyl, di(Ci_ 6 alkyl)aminoC 2 .
  • 6 alky 1, di(C ⁇ alky phosphony 1C ⁇ . 6 alkyl, hydroxyC 2 . 6 alkoxy, C 1 . 6 alkoxyC 2 - 6 alkoxy, aminoQ ⁇ alkyl, C].
  • 6 alky laminoC i . 6 alky 1, di(C i . 6 alkyl)aminoC i. 6 alky 1, di(C i. 6 alky l)aminoacety 1, aminoC 2 . 6 alkoxy, C i ⁇ alky laminoC 2 . 6 alkoxy, di(C . 6 allcy l)aminoC 2 _ 6 alkoxy, hydroxyC 2 .
  • the aryl refers to a C 6 _i 2 cyclic or bicyclic aromatic ring
  • heteroaryls each independently refer to a 5- to 12-membered cyclic or bicyclic aromatic hetero ring having one or more N, O or S;
  • the heterocycles each independently refer to a saturated or partially unsaturated 3- to 12-membered cyclic or bicyclic hetero ring having one or more N, O, S, SO or SO 2 , in which a carbon atom forming the heterocycle optionally has one or more substituents selected from the group consisting of C 1-6 alkyl, hydroxy, hydroxyCi -6 alkyl, hydroxycarbonyl, C 1 . 6 alkoxy, amino, Q. 6 alkylamino, diCC ⁇ alky ⁇ amino, di(Ci.6alkyl)aminoC 1-6 alkyl, di(C ! .
  • heterocycle optionally comprises a nitrogen atom
  • the nitrogen atom optionally has a substituent selected from the group consisting of hydrogen atom, C h alky 1, monohalogenoCi. 6 alkyl,
  • trihalogenoC 1-6 alkyl C 3 . 6 cycloalkyl, hydroxyC 2-6 alkyl, C 1 . 6 alkoxyC 2 . 6 alkyl, Ci. 6 alkylcarbonyl, hydroxyCi. 6 alkylcarbonyl, C 1-6 alkoxy carbonyl, carbamoyl, Ci_ 6 alkylcarbamoyl, d ⁇ C ⁇ alky ⁇ carbamoyl, sulfamoyl, C ⁇ alkylsulfamoyl, di(Ci. 6 alkyl)sulfamoyl, C 1-6 alkylsulfonyl, aminoC 2-6 alkyl, C 1-6 alkylaminoC 2 .
  • the Ci. 6 alkyl is partially unsaturated or has a C 3-6 cycloalkyl moiety, and a carbon atom in the heterocycle exists in a carbonyl form.
  • Fig. 1 size change of tumors by oral administration of the compound obtained in Example 2 in nude mice xenografted with NCI-H1975 cancer cells;
  • Z include substituents selected from the group consisting of formulae Zl to Z203, but are not limited thereto:
  • R is hydrogen, methyl, or ethyl
  • the compound of formula (IV) is reacted with Z-NH 2 in an alcohol solution (e.g., 2-propanol or 2-butanol) in the presence of an inorganic acid (e.g., hydrochloric acid) or organic acid (e.g., trifluoroacetic acid) at a temperature ranging from 70°C to reflux temperature; or with Z-NH 2 in an organic solvent (e.g., 1,4-dioxane) in the presence of a palladium catalyst (e.g., palladium (II) acetate or tris(dibenzylidenacetone)dipalladium(0), and in the presence of a ligand (e.g., bis(diphenylphosphino)(Xanthene)(Xantphos) or 2,2'- bis(disphenylphosphino)-l,l'-binaphthyl (BINAP)) and an inorganic base (e.g., cesium carbonate or sodium
  • the aniline compound of formula (II) is subjected to a reaction with an acryloyl chloride substituted with A and B, in an organic solvent (e.g., methylene chloride or tetrohydrofuran) or a mixed solvent such as 50% aqueous tetrahydrofuran in the presence of an inorganic base (e.g., sodium bicarbonate) or organic base (e.g., triethylamine or diisopropylethylamine) at a low temperature ranging from -10°C to 10°C; or with acrylic acid substituted with A and B, in pyridine using a coupling agent (e.g., l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDCI) or 2-(lH-7-azabenzotriazol-l-yl)- 1, 1,3,3-tetramethyl uronium hexafluoro phosphate methaneaminium (
  • an organic solvent
  • the present invention provides a pharmaceutical composition for preventing or treating cancers, tumors, inflammatory diseases, autoimmune diseases, or immunologically mediated diseases which comprises the inventive compound as an active ingredient.
  • the therapeutic agent for treating the inflammatory diseases, autoimmune diseases, or immunologically mediated diseases may include, but are not limited to, steroid drugs (e.g., prednisone, prednisolone, methyl prednisolone, cortisone, hydroxycortisone, betametasone, dexametasone and the like), methotrexates, leflunomides, anti-TNFa agents (e.g., etanercept, infliximab, adalimunab and the like), calcineurin inhibitors (e.g., tacrolimus, pimecrolimus and the like) and antihistaminic drugs (e.g., diphenhydramine, hydroxyzine, loratadine, ebastine, ketotifen, cetirizine, levocetirizine, fexofenadine and the like), and at least one therapeutic agent selected therefrom may be included in the inventive pharmaceutical composition.
  • Step 1 The compound (3.2 g, 19.4 mmol) obtained in Step 1 was dissolved in phosphorous oxy chloride (12 mL) and refluxed with stirring for 3 hours at 200 °C. After the reaction was complete, the reaction mixture was cooled to room temperature and added dropwise to 4 °C distilled water with stirring vigorously. The resulting solid was filtered under a reduced pressure with washing using distilled water, and the resulting solid was dried under a reduced pressure to obtain the title compound (yield: 2.9 g, 73.3 %).
  • Example 1 The procedure of Example 1 was repeated except for using various amine derivatives represented by Z-NH 2 (Z is the same as defined above) instead of 4-(4-methylpiperazin-l-yl)benzeneamine in Step 4 to prepare the compounds of Examples 2 to 156 which are shown in Tables la to lv below.
  • Example 157 Preparation of 7Y-(3-(2-(4-(4-methyl-4-oxy-piperaziii-l-yl)- phenylamino)-thieno[3,2- ⁇ /]pyrimidine-4-yIoxy)-phenyl)-acrylamide
  • Example 158 Preparation of iV-(3-(2-(4-(piperazin-l-yi)phenylamino)- thieno [3,2-d] py rimidine-4-y loxy)-pheny l)-acry lamide
  • Step 4 of Example 1 The procedure of Step 4 of Example 1 was repeated except for using tert-bu y ⁇ 4-(4-aminophenyl)piperazin-l-carboxylate instead of 4-(4- methylpiperazin-l-yl)benzeneamine to obtain the title compound (yield: 610 mg,
  • Example 158 The procedure of Example 158 was repeated except for using ieri-butyl 4-(4-amino-2-chlorophenyl)piperazin-l-carboxylate or [l-(4- aminophenyl)cyclopropyl]carbamic acid feri-butyl ester instead of tert-bu yl 4- (4-aminophenyl)piperazin-l-carboxylate in Step 4, to prepare the compounds of Examples 159 and 160 which are shown in Table 2 below.
  • Example 161 The procedure of Example 161 was repeated except for using trans-3- chloroacrylic acid and (£)-4-(dimethylamino)-2-butenoic acid to prepare the compounds of Examples 162 and 163 which are shown in Table 3 below.
  • Example 164 A similar procedure as the procedure of Example 164 was carried out except for using 2-fluoro-5-nitrophenol and 2-methoxy-5-nitrophenol, to obtain compounds of Example 165 and Example 166, respectively.
  • step 5) and 6) of Example 1 were repeated sequentially except for using the compound obtained in the step 1) (1.35 mmol), instead of N-(4-(4-methylpiperazin- 1 -yl)phenyl)-4-(3-nitrophenoxy)thieno[3 ,2- d]pyrimidin-2-amine, to obtain 50 mg of the title compound (final yield: 34 %).
  • Example 167 or a similar procedure was repeated except for using various amine derivatives of Z-NH 2 (Z has the same meaning as defined in the present invention), instead of 5-(4-methylpiperazin-l-yl)piridin- 2-amine in step 1) of Example 167, to obtain the title compounds of Examples 168 to 205 as shown in Tables 5a to 5f.
  • Example 1 The procedure of Example 1 was repeated except for using 3- nitrobenzeneamine (0.05 mmol), instead of 3-nitrophenol in step 3) of Example 1, to obtain 5 mg of the title compound (final yield: 55 %).
  • Example 206 The procedure of Example 206 or a similar procedure was repeated except for using various amine derivatives of Z-NH 2 (Z has the same meaning as defined in the present invention), instead of 5-(4-methylpiperazin-l-yl)piridin- 2-amine in Example 1, to obtain the title compounds of Examples 207 to 217 as shown in Tables 6a and 6b.
  • Example 218 Preparation of A ⁇ -(4-fluoro-3-(2-(4-(4-methyl-piperazin-l-yl)- phenylamino -thieno[3,2-i Ipyrimidin-4-ylamino)-phenyl)-acrylamide
  • Step P Preparation of N-(4-fluoro-3-nitro-phenyl)-acrylamide 2 g (12.81 mmol) of 4-fluoro-3-nitroaniline and 3.2 g (38.43 mmol) of sodium bicarbonate were diluted in 20 mL of tetrahydrofuran and 5 mL of distilled water, and 1.14 mL (14.09 mmol) of acryloyl chloride was slowly added thereto at 0 ° C , and stirred for 1 hour. Upon the completion of the reaction, the resulting mixture was diluted with ethylacetate and washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was separated, dried over anhydrous Na 2 SO 4 , and filtered and distilled under a reduced pressure to obtain 2 g of the title compound (yield: 74 %).
  • Step 4) Preparation of N-(4-fluoro-3-(2-(4-(4-methyl-piperazin-l-yn- phenylamino -thieno 3,2- ⁇ lpyrimidin-4-ylamino -phenyl)-acrylamide 100 mg (0.30 mmol) of the compound obtained in the Step 3) was dissolved in 3 ml of 2-butanol, and 55 mg (0.28 mmol) of 4-(4-methylpiperazin- l-yl)benzeneamine and 42 ⁇ (0.57 mmol) of trifluoroacetic acid were added thereto, and stirred for 5 hours at 100 ° C .
  • Example 218 A similar procedure as the procedure of Step 4) of Example 218 was carried out except for using 3-fluoro-4-(4-methylpiperazin-l-yl)anilline (0.03 mmol), instead of 4-(4-methylpiperazin-l-yl)benzeneamine in the Step 4) of Example 218, to obtain 8 mg of the title compound (final yield: 50%).
  • Example 220 Preparation of A ⁇ (3-(2-(4-dimethylaminomethyl- phenylamino)-thieno[3,2- ⁇ ]pyrimidin-4-ylamino)-phenyl)-acrylamide
  • Test Example 1 Inhibition test for growth of cancer cell expressing EGFR
  • the inhibiting test of the inventive compounds on the cancer cell growth was conducted in A431 (ATCC CRL-1555), HCC827 (ATCC CRL- 2868) and NCI-H1975 (ATCC CRL-5908) cell lines.
  • the cancer cell lines stored in a liquid nitrogen tank were each quickly thawed at 37°C, and centrifuged to remove the medium.
  • the resulting cell pellet was mixed with a culture medium, incubated in a culture flask at 37°C under 5% CO 2 for 2 to 3 days, and the medium was removed.
  • the remaining cells were washed with DPBS (Dulbecco's Phosphate Buffered Saline) and separated from the flask by using Tripsin-EDTA.
  • the separated cells were diluted with a culture medium to a concentration of 1 X 10 5 A431 cells/ml, except that in case of HCC827 and NCI-H1975 cells, the dilution was carried out to 5 X 10 4 cells/ml.
  • the compounds obtained in Examples 1 to 237 were each dissolved in 99.5% dimethylsulfoxide (DMSO) to a concentration of 25 mM.
  • DMSO dimethylsulfoxide
  • 1% HC1 was added thereto and treated in a 40°C water bath for 30 mins until a complete dissolution was attained.
  • the DMSO solution containing test compound was diluted with a culture medium to a final concentration of 100 ⁇ , and then diluted 10 times serially to 10 "6 ⁇ (a final concentration of DMSO was less than 1%).
  • GI 50 the concentration at which 50% inhibition occurs, was evaluated based on the difference between the final density of the test cells and the initial density of the cells incubated in a well not-treated with the test compound which was regarded as 100%.
  • the calculation of GI 50 and the result analysis were carried out by using Microsoft Excel, and the results are shown in Tables 14a to 14f.
  • A means that GI 50 ⁇ 50 nM
  • B means that GI 50 is 50-100 nM
  • C means that GI 50 is 100- 1 ,000 nM
  • D means that GI 50 > 1 ,000 nM.
  • such irreversible inhibitor having the quinazoline structure may cause serious adverse side effects (e.g., diarrhea, skin rash and weight loss) when treated in an amount for inhibiting EGFR T790M, and therefore, there still has been a need to develop a safe drug for overcoming the problems of the resistance development of EGFR T790M.
  • the inhibiting activity of the test compounds against the kinases was determined as a phosphorylation percentage (%) compared with control group, according to the kit protocol, and measured for IC 50 , the concentration of x-axis at which 50% inhibition was observed.
  • the calculation of IC 5 o and the result analysis were carried out by using Microsoft Excel. The results are shown in Table 15. Wherein, A means that IC 50 ⁇ 50 nM, B means that IC 50 is 50-100 nM, C means that IC 50 is 100-1,000 nM, and D means that IC 50 > 1 ,000 nM.
  • the inventive compounds are effective and safe drug employable to NSCLC patients by showing an effectively excellent inhibition activity against EGFR mutants including EGFR T790M with no inhibition activity against EGFR WT expressed in normal cell.
  • Test Example 3 Inhibition test for activities of BTK and JAK3 kinase
  • Test Example 4 Inhibition test for activities of BMX, ITX and RLK kinases
  • Example 1 The compound obtained in Example 1 was measured for its inhibitory activity on TEC family kinases, i.e., BMX, ITK, TEX and RLK. The measurement was carried out in the same process as in Example 2, except for using BMX, ITK, TEC and RLK enzymes (Invitrogen) instead of EGFR enzyme.
  • BMX, ITK, TEC and RLK enzymes Invitrogen
  • Table 17 The results are shown in Table 17.
  • TEC family kinases such as BTK, BMX, ITK, and RLK kinases
  • Test Example 5 Anticancer efficacy test in nude mice xenografted with NCI- H1975 cancer cells
  • Example 2 The compound according to the present invention (Example 2) was tested for its anticancer effect and toxicity in nude mice xenografted with NCI-H1975 cancer cells which shows resistance to Erlotinib previously approved for the treatment of non-small cell lung cancer, due to the acquisition of EGFR T790M point mutation.
  • BIBW2992 Boehringer Ingelheim
  • NCI-H1975 cell lung cancer cell
  • ATCC American Type Culture Collection
  • a tumor in the sixth generation isolated from an individual was cut into a size of 30 mg, and transplanted subcutaneously into right flanks of mice using a 12-gauge trocar.
  • the volume of tumor (V) is calculated from following equation 1 after measuring a long diameter (L) and a short diameter (S) using a vernier caliper twice a week for 18 days of test. All test materials were orally administered one time a day for total 10 days, and the tumor growth inhibition rate (IR: tumor growth inhibition rate (%) calculated based on a vehicle-treated control) and the maximum body weight loss (mBWL: maximum body weight loss calculated based on the body weight just before administration) were calculated using following equations 2 and 3. The results are shown in Table 6 and Figs. 1 and 2.
  • IR (%) (1-(RTG of the treatment group of test material)/(RTG of the control group)) ⁇ 100
  • RTG is a relative tumor growth, which is the mean tumor volume on a particular day based on daily mean tumor volume.
  • day x is a day on which the body weight loss is largest during the test.
  • the compound of the present invention did not inhibit EGFR WT and exhibited an excellent activity on EGFR mutant specific to non-small cell lung cancer (active mutant: EGFR DelR746_A750, EGFR L858R; acquired mutation: EGFR T790M).
  • active mutant EGFR DelR746_A750, EGFR L858R; acquired mutation: EGFR T790M.
  • the CIA model is a widely used, representative autoimmune arthritis model, arthritis of which is induced by injecting a mixture of type II collagen and an immunologic adjuvant to a specific mouse strain having major histocompatability complex (MHC) class II with H-2 q or H-2 r and thus CD4+ T cells and B-cells specifically responsive to the type II collagen are abnormally activated.
  • MHC major histocompatability complex
  • mice Male DBA/IJ mice (8 weeks old) were first immunized by intradermal injection of 0.7 mL of a suspension liquid in which an equal volume of 2 mg/mL of type II collagen is emulsified in 4 mg/mL of complete Freund's adjuvant supplemented with bacteria tuberculosis. After 21 days, the mice were second immunized by the injection as above, except for using a suspension liquid in which an equal volume of 2 mg/mL of type II collagen is emulsified in incomplete Freund's adjuvant containing no bacteria tuberculosis. After 1 week of second immunization, mice were evaluated for clinical scores based on Table 10 and seven animals were grouped such that the average of experimental group is between 1 and 2.
  • Test samples and vehicle of given concentrations were orally administered in an amount of 10 mL per body weight for 14 days everyday by using a Sonde.
  • the clinical scores of arthritis (David D Brand et al., Nature Protocol. 2(5), 1269, 2007) were evaluated three times a day.
  • Example 1 reduced edema and flare until the last day (14 days) of the test in 10 mg/kg and 30 mg/kg groups compared to a control group, and significantly reduced edema, inflammation and flare in a 30 mg/kg group (Fig. 3).
  • the compound according to the present invention inhibited the activities of BTK and JAK3 kinases, and the inhibitions reduced edema, inflammation and flare as well as anti-collagen antibody values in a CIA model of autoimmune arthritis, compared to a control group, and also reduced the formation of pannus in histopathologic testing.
  • the above results in a rodent model of arthritis suggest that the compound according to the present invention may provide clinical effects for patients with rheumatoid arthritis.
  • the compound according to the present invention significantly reduced the secretion of interleukin-6 (IL-6) and TNF-a in human peripheral blood mononuclear cells (PBMCs) and mouse splenocytes abundant in T- lymphocytes, B-lymphocytes, Cytes and macrophages after treatment of phorbol- 12-myristate- 13 -acetate (PMA), phytohemagglutinin (PHA), lonomycin, and others which stimulate lymphocytes, compared to a control group.
  • PMA phorbol- 12-myristate- 13 -acetate
  • PHA phytohemagglutinin
  • lonomycin lonomycin

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Abstract

La présente invention concerne un nouveau dérivé fusionné de pyrimidine ayant une activité inhibitrice pour les tyrosines kinases et une composition pharmaceutique pour la prévention ou le traitement de cancers, de tumeurs, de maladies inflammatoires, de maladies auto-immunes ou de maladies immunologiques comprenant celui-ci comme principe actif.
EP11798350.2A 2010-06-23 2011-06-20 Nouveaux dérivés fusionnés de pyrimidine pour l'inhibition de l'activité tyrosine kinase Active EP2585470B1 (fr)

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SI201131094A SI2585470T1 (sl) 2010-06-23 2011-06-20 Novi fuzirani derivati pirimidina za inhibicijo aktivnosti tirozin kinaze
RS20170267A RS55783B1 (sr) 2010-06-23 2011-06-20 Novi derivati fuzionisanog pirimidina za inhibiciju aktivnosti tirozin kinaze
PL15181011T PL2975042T3 (pl) 2010-06-23 2011-06-20 Nowe pochodne skondensowanych pirymidyn do hamowania aktywności kinaz tyrozynowych
PL11798350T PL2585470T3 (pl) 2010-06-23 2011-06-20 Nowe sprzężone pochodne pirymidyny do hamowania aktywności kinazy tyrozynowej
EP15181011.6A EP2975042B1 (fr) 2010-06-23 2011-06-20 Nouveaux dérivés fusionnés de pyrimidine pour l'inhibition de l'activité tyrosine kinase
HRP20170456TT HRP20170456T1 (hr) 2010-06-23 2017-03-20 Novi kondenzirani derivati pirimidina, namijenjeni inhibiranju aktivnosti tirozinske kinaze

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US9273077B2 (en) 2008-05-21 2016-03-01 Ariad Pharmaceuticals, Inc. Phosphorus derivatives as kinase inhibitors
CN102159214A (zh) 2008-07-16 2011-08-17 药品循环公司 用于实体肿瘤的治疗的布鲁顿酪氨酸激酶的抑制剂
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US9345719B2 (en) 2016-05-24
MY162132A (en) 2017-05-31
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TR201821217T4 (tr) 2019-01-21
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SG186378A1 (en) 2013-01-30
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MY174196A (en) 2020-03-13
BR122014012788B1 (pt) 2022-04-19
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CN105061438B (zh) 2017-07-04
RS55783B1 (sr) 2017-07-31
RU2585177C2 (ru) 2016-05-27
TW201443059A (zh) 2014-11-16
IL232382A (en) 2016-12-29
TW201204364A (en) 2012-02-01
WO2011162515A3 (fr) 2012-05-03
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DK2975042T3 (en) 2019-01-21
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EP2585470B1 (fr) 2017-01-25
UA108889C2 (uk) 2015-06-25
PL2975042T3 (pl) 2019-07-31
AU2011269989B2 (en) 2014-12-11
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LT2975042T (lt) 2019-01-25
SI2975042T1 (sl) 2019-02-28
HRP20190012T1 (hr) 2019-02-22
AU2011269989A8 (en) 2013-02-28
PH12012502431A1 (en) 2013-07-08
US20150045324A1 (en) 2015-02-12
WO2011162515A2 (fr) 2011-12-29
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US20160229868A1 (en) 2016-08-11
BR112012033253A2 (pt) 2016-11-22
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CN102947316A (zh) 2013-02-27
MX342164B (es) 2016-09-19
JP5852173B2 (ja) 2016-02-03
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CN102947316B (zh) 2016-08-10
AR096075A2 (es) 2015-12-02
US8957065B2 (en) 2015-02-17
IL223689A (en) 2017-03-30
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